Protein Homeostasis: Its Role in Aging and Diseases

Protein Homeostasis: Its Role in Aging and Diseases
Protein homeostasis and its role in aging and diseases

Pierre Goloubinoff: Aging is a natural and necessary degenerative process of somatic cells that leads to death. Young embryonic, germ, and cancer cells are potentially immortal. This is due to their ability to massively produce optimal defense for the protection, repair, and replacement of delicate macromolecules.

Cellular system of work

When exiting ribosomes, new polypeptides must fold properly, eventually translocate, and then assemble into stable yet functionally flexible structures. During their lifetime, proteins are often exposed to stresses such as heat shock, ultraviolet radiation, and oxidative stress. This can partially unfold and convert them into a stable misfolded and aggregated form.

This can, in turn, lead to cell damage and spread to other cells, as in the case of some prion diseases. In animal cells, especially aging neurons, early forms of toxic protein aggregates can accumulate and cause cell death on their way to becoming more compact clumps and amyloids, which are less toxic. In mammals, cumulative toxicity can lead to tissue loss through various mechanisms, including direct membrane damage, as well as reactive oxygen species that alter lipids and signal for apoptosis.

Programmed cell death can thus trigger, in this way, the early onset of aging and degenerative diseases in general, such as:

  • Alzheimer's disease
  • Type 2 diabetes
  • Amyotrophic lateral sclerosis
  • Parkinson's disease

This will ultimately lead to a reduction in life expectancy.

In young age and healthy adult life, protein homeostasis and the main cellular mechanisms for effective quality control are:

  1. Molecular chaperones, acting as a filler of unfolding and folding enzymes.
  2. Chaperones of closed-form proteases, acting collectively of unfolding and degrading enzymes.
  3. Aggresomes, acting as a collective of compaction mechanisms.
  4. Autophagy, acting as an aggregate-degrading organelle.

For unclear reasons, these cellular protective functions gradually become dysfunctional. Protein homeostasis works worse with age, leading to the development of degenerative diseases associated with misfolded protein folding. Understanding these protective mechanisms and the reasons for their dysfunction at the end of adult life is the key to developing new treatments for degenerative proteins misfolding, diseases, and aging.

It has been observed that many cancer cells resemble young cells and are immortal due to their massive overexpression of molecular chaperones, Hsp70 and HSP90 in particular, which can block beneficial apoptosis in response to various radio-, thermo-, and chemotherapeutic procedures. Thus, chaperone inhibitors are promising for improving the efficacy of classical treatments against cancer tissues, provided that they can be prevented from unhinging protein aggregation, degenerative diseases, and aging in healthy tissues.